Parallel hippocampal-parietal circuits for self- and goal-oriented processing.

The hippocampus is critically important for a diverse range of cognitive processes, such as episodic memory, prospective memory, affective processing, and spatial navigation. Using individual-specific precision functional mapping of resting-state functional MRI data, we found the anterior hippocampus (head and body) to be preferentially functionally connected to the default mode network (DMN), as expected. The hippocampal tail, however, was strongly preferentially functionally connected to the parietal memory network (PMN), which supports goal-oriented cognition and stimulus recognition. This anterior-posterior dichotomy of resting-state functional connectivity was well-matched by differences in task deactivations and anatomical segmentations of the hippocampus. Task deactivations were localized to the hippocampal head and body (DMN), relatively sparing the tail (PMN). The functional dichotomization of the hippocampus into anterior DMN-connected and posterior PMN-connected parcels suggests parallel but distinct circuits between the hippocampus and medial parietal cortex for self- versus goal-oriented processing.

Individualized Functional Subnetworks Connect Human Striatum and Frontal Cortex.

The striatum and cerebral cortex are interconnected via multiple recurrent loops that play a major role in many neuropsychiatric conditions. Primate corticostriatal connections can be precisely mapped using invasive tract-tracing. However, noninvasive human research has not mapped these connections with anatomical precision, limited in part by the practice of averaging neuroimaging data across individuals. Here we utilized highly sampled resting-state functional connectivity MRI for individual-specific precision functional mapping (PFM) of corticostriatal connections. We identified ten individual-specific subnetworks linking cortex-predominately frontal cortex-to striatum, most of which converged with nonhuman primate tract-tracing work. These included separable connections between nucleus accumbens core/shell and orbitofrontal/medial frontal gyrus; between anterior striatum and dorsomedial prefrontal cortex; between dorsal caudate and lateral prefrontal cortex; and between middle/posterior putamen and supplementary motor/primary motor cortex. Two subnetworks that did not converge with nonhuman primates were connected to cortical regions associated with human language function. Thus, precision subnetworks identify detailed, individual-specific, neurobiologically plausible corticostriatal connectivity that includes human-specific language networks.

Default-mode network streams for coupling to language and control systems.

The human brain is organized into large-scale networks identifiable using resting-state functional connectivity (RSFC). These functional networks correspond with broad cognitive domains; for example, the Default-mode network (DMN) is engaged during internally oriented cognition. However, functional networks may contain hierarchical substructures corresponding with more specific cognitive functions. Here, we used individual-specific precision RSFC to test whether network substructures could be identified in 10 healthy human brains. Across all subjects and networks, individualized network subdivisions were more valid-more internally homogeneous and better matching spatial patterns of task activation-than canonical networks. These measures of validity were maximized at a hierarchical scale that contained ∼83 subnetworks across the brain. At this scale, nine DMN subnetworks exhibited topographical similarity across subjects, suggesting that this approach identifies homologous neurobiological circuits across individuals. Some DMN subnetworks matched known features of brain organization corresponding with cognitive functions. Other subnetworks represented separate streams by which DMN couples with other canonical large-scale networks, including language and control networks. Together, this work provides a detailed organizational framework for studying the DMN in individual humans.

Individual-specific functional connectivity of the amygdala: A substrate for precision psychiatry.

The amygdala is central to the pathophysiology of many psychiatric illnesses. An imprecise understanding of how the amygdala fits into the larger network organization of the human brain, however, limits our ability to create models of dysfunction in individual patients to guide personalized treatment. Therefore, we investigated the position of the amygdala and its functional subdivisions within the network organization of the brain in 10 highly sampled individuals (5 h of fMRI data per person). We characterized three functional subdivisions within the amygdala of each individual. We discovered that one subdivision is preferentially correlated with the default mode network; a second is preferentially correlated with the dorsal attention and fronto-parietal networks; and third subdivision does not have any networks to which it is preferentially correlated relative to the other two subdivisions. All three subdivisions are positively correlated with ventral attention and somatomotor networks and negatively correlated with salience and cingulo-opercular networks. These observations were replicated in an independent group dataset of 120 individuals. We also found substantial across-subject variation in the distribution and magnitude of amygdala functional connectivity with the cerebral cortex that related to individual differences in the stereotactic locations both of amygdala subdivisions and of cortical functional brain networks. Finally, using lag analyses, we found consistent temporal ordering of fMRI signals in the cortex relative to amygdala subdivisions. Altogether, this work provides a detailed framework of amygdala-cortical interactions that can be used as a foundation for models relating aberrations in amygdala connectivity to psychiatric symptoms in individual patients.

Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

Histopathologic features of necrobiosis lipoidica.

BACKGROUND: Necrobiosis lipoidica (NL) is an uncommon granulomatous dermatosis that can occur in patients with or without associated diabetes mellitus (DM). Prior studies have attempted to determine distinctive histopathologic features of NL in patients with and without DM. METHODS: A retrospective review of 97 patients with NL was performed to determine the similar and distinctive histopathologic features in patients with DM and without DM. RESULTS: Of the 97 patients, 32% (n = 31) had DM. Epidermal acanthosis was seen more commonly in diabetics than nondiabetics (32.3% vs. 12.1%; p = 0.017). Naked (sarcoidal/tuberculoid) granulomas were more frequently observed in nondiabetics than diabetics (22.7% vs. 3.2%; p = 0.016). Eosinophils were more common in nondiabetics than diabetics (38.5% vs. 9.7%; p = 0.004), while neutrophilic infiltration was more common in diabetics than nondiabetics (45.2% vs. 17.5%; p = 0.004). CONCLUSIONS: This study corroborates well-documented histopathologic features of NL and shows distinctive histopathologic features of NL among patients with DM-I, DM-II, and without DM. These results support the hypothesis that there are different underlying drivers of NL between diabetics and nondiabetics.

Trait-like variants in human functional brain networks.

Resting-state functional magnetic resonance imaging (fMRI) has provided converging descriptions of group-level functional brain organization. Recent work has revealed that functional networks identified in individuals contain local features that differ from the group-level description. We define these features as network variants. Building on these studies, we ask whether distributions of network variants reflect stable, trait-like differences in brain organization. Across several datasets of highly-sampled individuals we show that 1) variants are highly stable within individuals, 2) variants are found in characteristic locations and associate with characteristic functional networks across large groups, 3) task-evoked signals in variants demonstrate a link to functional variation, and 4) individuals cluster into subgroups on the basis of variant characteristics that are related to differences in behavior. These results suggest that distributions of network variants may reflect stable, trait-like, functionally relevant individual differences in functional brain organization.

Health and nutrition of loggerhead sea turtles (Caretta caretta) in the southeastern United States.

Loggerhead sea turtles (Caretta caretta) are opportunistic carnivores that feed primarily on benthic invertebrates and fish. Sea turtle rehabilitation requires provision of a species-specific, balanced diet that supplies nutrition similar to that of a wild diet; this can be challenging because free-ranging loggerheads' diets vary depending on their life stage and geographic location, with predominant prey species dictated by local availability. The goal of this study was to better understand the nutritional needs of subadult and adult loggerheads in rehabilitation. This was accomplished by conducting a retrospective survey of stomach contents identified during gross necropsy of 153 deceased loggerheads that stranded in coastal Georgia, USA. A total of 288 different forage items were identified; the most frequently observed prey items belong to the subphylum Crustacea (N = 131), followed by bony fish (Osteichthyes; N = 45), gastropod mollusks (N = 40), bivalve mollusks (N = 23), and Atlantic horseshoe crabs (Limulus polyphemus; N = 15). The proportions of certain prey items differed significantly with turtle size; adult turtles ate proportionately more gastropods (p = 0.001), and subadults ate proportionately more fish (p = 0.01). Stomach contents information was used to determine common local prey items (blue crab, cannonball jellyfish, horseshoe crab, whelk), which were evaluated for nutritional content. Additionally, we compared hematology and plasma biochemistry profiles (including proteins, trace minerals, and vitamins) between four cohorts of loggerhead turtles, including free-ranging subadults and adults, nesting females, and loggerheads undergoing rehabilitation. This information was applied to inform a regionally specific, formulated diet for tube feeding, and a supplement containing vitamins and minerals for captive loggerheads, to more closely approximate the nutritional content of their natural diet. Assessing the regional and temporal variability in loggerhead diets is an important component in their effective conservation because resultant data can be used to help understand the impacts of environmental perturbations on benthic food webs.

A rare case of childhood mucous membrane pemphigoid involving the oral and genital mucosa.

Mucous membrane pemphigoid (MMP) is a rare chronic immunobullous disease that involves the mucous membranes and may result in significant scarring and complications if diagnosis is delayed. MMP typically occurs in elderly patients, with very few cases reported in children. Here, we present a 12-year-old female patient with childhood-onset oral and genital MMP, clinically suspected to be lichen sclerosus, but eventually diagnosed as MMP after multiple supportive biopsies and confirmatory direct immunofluorescence. Although treatment was challenging, the combined use of systemic corticosteroids, dapsone, and mycophenolate mofetil was ultimately successful in achieving disease control.

Prognostic value of inositol polyphosphate-5-phosphatase expression in recurrent and metastatic cutaneous squamous cell carcinoma.

BACKGROUND: Inositol polyphosphate-5-phosphatase (INPP5A) has been shown to play a role in the progression of actinic keratosis to cutaneous squamous cell carcinoma (cSCC) and the progression of localized disease to metastatic disease. Currently, no cSCC biomarkers are able to risk stratify recurrent and metastatic disease. OBJECTIVE: To determine the prognostic value of INPP5A expression in cSCC recurrent and metastatic disease. METHODS: We conducted a multicenter, single-institutional, retrospective cohort study within the Mayo Clinic Health System on the use of immunohistochemical staining to examine cSCC INPP5A protein expression in primary tumors and recurrent and metastatic disease. Dermatologists and dermatopathologists were blinded to outcome. RESULTS: Low staining expression of INPP5A in recurrent and metastatic disease tumors was associated with poor overall survival (OS) (31.0 months for low versus 62.0 months for high expression; P = .0272). A composite risk score (calculated as score of primary tumor + score of recurrent or metastatic disease tumor, with tumors with high expression scoring a zero and low expression a 1, score range 0-2) of 0 was predictive of improved OS compared with a composite risk score of ≥1 (hazard ratio 0.42, 95% confidence interval 0.21-0.84; P = .0113). LIMITATIONS: This is a multicenter but single institution study of a white population. CONCLUSION: Loss of INPP5A expression predicts poor OS in recurrent and metastatic disease of cSCC.

Cortisol as a Biomarker of Alcohol Use in Combat Veterans: A Literature Review and Framework for Future Research.

Objective: Alcohol use and alcohol use disorders (AUDs) are an increasing concern among veterans, particularly those from recent conflicts in Iraq and Afghanistan. The study of biomarkers in alcohol use and AUD has moved to enhancing the understanding of the development and maintenance of AUDs, as well as investigating its association with clinical severity and potential predictors of treatment response. Cortisol, a glucocorticoid known as a stress hormone, has been linked with both stress and trauma, as well as increased alcohol suppression effects. Method/Results: The present review summarizes existing literature and presents suggestions for future research to evaluate whether cortisol may be a possible biomarker of alcohol use disorder risk in combat veterans. Specifically, aspects of combat deployments and high levels of PTSD, coupled with the stress of reintegration may dysregulate cortisol and increase risk to AUD. There may also be bidirectional impacts, such that alcohol is used as a coping mechanism and can dysregulate hypothalamic pituitary adrenal (HPA) axis functioning and cortisol. Conclusions: In the context of this framework, cortisol may serve as a biomarker for the development of AUD, as well as a biomarker of risk or relapse. This review ends with both theoretical and clinical implications, as well as directions for future research.

Improving Access to Care Through the Establishment of a Local, Teledermatology Network.

Introduction: Access to dermatologic care is a major issue in the United States, especially within the un- and underinsured populations; technology, including teledermatology, will pay a role in improving access to care. Methods: We performed a prospective study between November 2016 and September 2017. We leveraged a partnership between Mayo Clinic and Mountain Park Health Clinic, a community clinic that primarily serves un- and underinsured populations. We implemented a mobile phone-based store and forward (SAF) teledermatology service, which integrated an external community health clinic to an existing electronic health record (EHR) using standardized data capture forms, real-time support, and simple workflows. Results: Thirty-seven patients were enrolled in the study, 65% female and 35% male with an average age of 47.9 (SD = 15.9). The ethnic breakdown was: 81.1% Hispanic, 13.5% Caucasian, and 5.4% African American. The majority, 62.2%, did not have a high school education, 45.9% were unemployed, and 51.4% were uninsured. 64.9% earned less than $25,000 for annual household income. Teledermatology consultation increased the absolute diagnostic and management concordance by 36.6% (p = 0.01, 95% CI 12.2%-61.0%) and 34.2% (p < 0.01, 95% CI 11%-57%), respectively. Primary care providers had a significant increase in mean confidence in the diagnosis and management of dermatology conditions pre and poststudy (3.60 vs. 3.70 and 3.21 vs. 3.60, respectively; p < 0.01). Ninety-six percent of the primary care providers agreed (52.0%) and strongly agreed (44.0%) that they would send another patient for teleconsultation.Conclusion: We successfully implemented a SAF teledermatology consultative service in a community health clinic outside our EHR. A similar approach can be used by other large health care organizations to provide integrated, high-quality consultation to clinics with rural, un- and underinsured populations.

MRI-based measures of intracortical myelin are sensitive to a history of TBI and are associated with functional connectivity.

Traumatic brain injuries (TBIs) induce persistent behavioral and cognitive deficits via diffuse axonal injury. Axonal injuries are often examined in vivo using diffusion MRI, which identifies damaged and demyelinated regions in deep white matter. However, TBI patients can exhibit impairment in the absence of diffusion-measured abnormalities, suggesting that axonal injury and demyelination may occur outside the deep white matter. Importantly, myelinated axons are also present within the cortex. Cortical myelination cannot be measured using diffusion imaging, but can be mapped in-vivo using the T1-w/T2-w ratio method. Here, we conducted the first work examining effects of TBI on intracortical myelin in living humans by applying myelin mapping to 46 US Military Veterans with a history of TBI. We observed that myelin maps could be created in TBI patients that matched known distributions of cortical myelin. After controlling for age and presence of blast injury, the number of lifetime TBIs was associated with reductions in the T1-w/T2-w ratio across the cortex, most significantly in a highly-myelinated lateral occipital region corresponding with the human MT+ complex. Further, the T1-w/T2-w ratio in this MT+ region predicted resting-state functional connectivity of that region. By contrast, a history of blast TBI did not affect the T1-w/T2-w ratio in either a diffuse or focal pattern. These findings suggest that intracortical myelin, as measured using the T1-w/T2-w ratio, may be a TBI biomarker that is anatomically complementary to diffusion MRI. Thus, myelin mapping could potentially be combined with diffusion imaging to improve MRI-based diagnostic tools for TBI.

High-fidelity mapping of repetition-related changes in the parietal memory network.

fMRI studies of human memory have identified a "parietal memory network" (PMN) that displays distinct responses to novel and familiar stimuli, typically deactivating during initial encoding but robustly activating during retrieval. The small size of PMN regions, combined with their proximity to the neighboring default mode network, makes a targeted assessment of their responses in highly sampled subjects important for understanding information processing within the network. Here, we describe an experiment in which participants made semantic decisions about repeatedly-presented stimuli, assessing PMN BOLD responses as items transitioned from experimentally novel to repeated. Data are from the highly-sampled subjects in the Midnight Scan Club dataset, enabling a characterization of BOLD responses at both the group and single-subject level. Across all analyses, PMN regions deactivated in response to novel stimuli and displayed changes in BOLD activity across presentations, but did not significantly activate to repeated items. Results support only a portion of initially hypothesized effects, in particular suggesting that novelty-related deactivations may be less susceptible to attentional/task manipulations than are repetition-related activations within the network. This in turn suggests that novelty and familiarity may be processed as separable entities within the PMN.

The prognostic value of inositol polyphosphate 5-phosphatase in cutaneous squamous cell carcinoma.

BACKGROUND: Inositol polyphosphate 5-phosphatase (INPP5A) has been shown to play a role in development and progression of cutaneous squamous cell carcinoma (cSCC). The goal of the current study was to explore the prognostic value of INPP5A expression in cSCC. METHODS: A total of 189 cases of actinic keratosis and SCC in 174 patients were identified; clinical and outcome data were abstracted, histopathology was rereviewed, and immunohistochemical staining and interpretation was performed for INPP5A. RESULTS: The majority of tumors (89.4%) had an INPP5A score of 2 or 3. No patients had complete loss of INPP5A. Tumors with an INPP5A score of 1 were more likely to be intermediate- to high-risk tumors (Brigham and Women's Hospital stage ≥T2a 85.0% vs 23.7% [P < .0001]) characterized by a larger diameter (2.4 cm vs 1.3 cm [P = .0004]), moderate-to-poor differentiation (86.7% vs 17.6% [P < .0001]), and perineural invasion (37.5% vs 5.3%, [P < .0001]). An INPP5A score of 1 was associated with a worse 3-year survival (a rate of 42.3% [hazard ratio, 2.81, P = .0006]) and a local metastasis rate of 48.0% (hazard ratio, 4.71; P < .0001). CONCLUSIONS: Low INPP5A scores are predictive of aggressive tumors and may be a useful adjunct to guide clinical management of cSCC.

BOLD Activity During Correct-Answer Feedback in Cued Recall Predicts Subsequent Retrieval Performance: An fMRI Investigation Using a Partial Trial Design.

Receiving correct answer feedback following a retrieval attempt has proven to be a highly effective means of learning new information, yet the mechanisms behind its efficacy remain poorly understood. Here, fMRI was used to examine how BOLD activity measured during a period of feedback could predict subsequent memory (SM) performance on a final test. Twenty-five human subjects studied pairs of associated words, and were then asked to covertly recall target words in response to provided cues. Correct answer feedback was provided immediately after covert retrieval attempts. A partial trial design enabled separate modeling of activity related to retrieval and to feedback processing. During initial study, typical SM effects were observed across the whole brain. During feedback following a failed recall attempt, activity in only a subset of these regions predicted final test performance. These regions fell within the default mode network (DMN) and demonstrated negative SM effects, such that greater deactivation was associated with successful recall. No "task-positive" regions demonstrated SM effects in this contrast. The obtained results are consistent with a growing literature that associates DMN deactivation with successful learning in multiple task contexts, likely reflecting differences in the allocation of attentional resources during encoding.

Are There Multiple Kinds of Episodic Memory? An fMRI Investigation Comparing Autobiographical and Recognition Memory Tasks.

What brain regions underlie retrieval from episodic memory? The bulk of research addressing this question with fMRI has relied upon recognition memory for materials encoded within the laboratory. Another, less dominant tradition has used autobiographical methods, whereby people recall events from their lifetime, often after being cued with words or pictures. The current study addresses how the neural substrates of successful memory retrieval differed as a function of the targeted memory when the experimental parameters were held constant in the two conditions (except for instructions). Human participants studied a set of scenes and then took two types of memory test while undergoing fMRI scanning. In one condition (the picture memory test), participants reported for each scene (32 studied, 64 nonstudied) whether it was recollected from the prior study episode. In a second condition (the life memory test), participants reported for each scene (32 studied, 64 nonstudied) whether it reminded them of a specific event from their preexperimental lifetime. An examination of successful retrieval (yes responses) for recently studied scenes for the two test types revealed pronounced differences; that is, autobiographical retrieval instantiated with the life memory test preferentially activated the default mode network, whereas hits in the picture memory test preferentially engaged the parietal memory network as well as portions of the frontoparietal control network. When experimental cueing parameters are held constant, the neural underpinnings of successful memory retrieval differ when remembering life events and recently learned events.SIGNIFICANCE STATEMENT Episodic memory is often discussed as a solitary construct. However, experimental traditions examining episodic memory use very different approaches, and these are rarely compared to one another. When the neural correlates associated with each approach have been directly contrasted, results have varied considerably and at times contradicted each other. The present experiment was designed to match the two primary approaches to studying episodic memory in an unparalleled manner. Results suggest a clear separation of systems supporting memory as it is typically tested in the laboratory and memory as assessed under autobiographical retrieval conditions. These data provide neurobiological evidence that episodic memory is not a single construct, challenging the degree to which different experimental traditions are studying the same construct.

Learning Efficiency: Identifying Individual Differences in Learning Rate and Retention in Healthy Adults.

People differ in how quickly they learn information and how long they remember it, yet individual differences in learning abilities within healthy adults have been relatively neglected. In two studies, we examined the relation between learning rate and subsequent retention using a new foreign-language paired-associates task (the learning-efficiency task), which was designed to eliminate ceiling effects that often accompany standardized tests of learning and memory in healthy adults. A key finding was that quicker learners were also more durable learners (i.e., exhibited better retention across a delay), despite studying the material for less time. Additionally, measures of learning and memory from this task were reliable in Study 1 ( N = 281) across 30 hr and Study 2 ( N = 92; follow-up n = 46) across 3 years. We conclude that people vary in how efficiently they learn, and we describe a reliable and valid method for assessing learning efficiency within healthy adults.

Clinical and histopathologic features of paraneoplastic granuloma annulare in association with solid organ malignancies: A case-control study.

BACKGROUND: Granuloma annulare (GA) is a granulomatous skin eruption rarely associated with cancer. We report seven cases of paraneoplastic GA in association with solid organ malignancy. OBJECTIVE: To compare the clinical and histopathological features of paraneoplastic GA to case-matched controls of classic GA. METHODS: Retrospective chart and histopathological review of 7 individuals and 13 age- and sex-matched controls. Paraneoplastic GA was defined as GA occurring within 6 months of the diagnosis of solid organ malignancy and/or persistent GA that resolved with cancer treatment. RESULTS: Most cases of paraneoplastic GA were associated with lung cancer (4/7). The clinical and histopathological features of paraneoplastic and classic GA were similar. Compared to classic GA, paraneoplastic GA cases were more often generalized disease (6/7 vs 6/13), refractory to treatment, and had a perivascular inflammatory cell infiltrate (5/7 vs 2/13). All cases of paraneoplastic GA that underwent definitive treatment of their cancer improved. LIMITATIONS: Single-institution, retrospective review with a small sample size. CONCLUSION: Paraneoplastic GA is rare, similar to classic GA, and refractory to treatment. We advocate for age-appropriate screening in individuals with GA that is nonresponsive to multiple lines of systemic treatment and evaluating patients with concerning signs or symptoms for an underlying neoplasm.